The brain transduces sensory stimuli, processes information and stores memory within large networks of neurons linked together by synaptic connections. Our laboratory is working to understand what particular features of synapses affect their strength, reliability and independence, and how these attributes contribute to their role in the function of the network. Chemical synaptic connections are made through the release of diffusible neurotransmitter molecules that bind to receptors on the recipient neuron; recent evidence suggests that the neurotransmitter may escape the synapse in which it is released and diffuse into neighboring synapses. This "spillover" of neurotransmitter between synapses could have a profound impact on the information capacity of neural networks and the rules governing their construction during development. We have worked to determine the extent to which the excitatory neurotransmitter glutamate spills over between synapses in the hippocampus, a major site of learning and memory storage in the brain, and in the retina, where visual stimuli are encoded for transmission along the optic nerve. Using electrophysiological techniques in acutely prepared slices of rat retina and hippocampus, we have found that glutamate escapes the synapse from which it is released and diffuses into neighboring synapses. This diffusion is tightly regulated by glutamate transporters, pump proteins located primarily on glial membranes that bind glutamate and remove it from the extracellular fluid (Diamond, 2005). Work is continuing to investigate the modulation of these mechanisms and their impact on information processing in hippocampal and retinal neural networks. We have become particularly interested in how neuronal glutamate transporters, which are much less numerous than those on glia but nonetheless appear to limit epileptogenesis, contribute to the clearance of neurotransmitter and the specificity of synaptic connections. In the retina, we find that certain types of receptors may be localized specifically to limit their activation under certain conditions. On ganglion cells, NMDA-type glutamate receptors are located perisynaptically (Zhang and Diamond, 2006), such that their activation is prevented by glutamate transporters unless many vesicles of glutamate are released simultaneously. More recent work in the lab indicates that these perisynaptic receptors extend the range over which ganglion cells respond to light stimulation. We currently are exploring how NMDA receptors contribute differently to synaptic signaling in the ON and OFF retinal pathways. We also have increased our study of inhibitory synaptic connections made by amacrine cells within the inner retina, to understand how feedforward and feedback inhibition contributes to signal processing in this network. We find that A17 amacrine cells provide rapid GABAergic feedback to rod bipolar cell terminals via a release process that is independent of membrane depolarization or voltage-gated calcium channels (Chavez, et al., 2006). This rapid feedback, driven by activation of calcium-permeable AMPA receptors in the A17 amacrine cell, may be essential to prevent the rapid depletion of readily-releasable vesicles from the rod bipolar cell synaptic terminal (Singer and Diamond, 2006).